APPLICANT'S ABSTRACT: This competitive renewal proposes to continue a successful line of investigation examining the properties of opioid agonists, antagonists, and mixed agonist-antagonists in volunteer opioid abusers. These studies have examined the abuse liability of opioids, the optimal parameters for using opioids to treat opioid dependence, and the effectiveness and acceptability of novel formulations of opioids. Results from studies of buprenorphine, an opioid mixed agonist-antagonist, have been of particular interest since buprenorphine is being developed as a new treatment agent for opioid abuse by the National Institute on Drug Abuse (NIDA). While buprenorphine is a promising new medication for treating opioid dependence, it must be taken sublingually because of its poor oral bioavailability. This formulation may be abused parenterally, and because of this potential NIDA is interested in developing buprenorphine as a combination product that includes naloxone. Ideally, a buprenorphine/naloxone combination product would produce precipitated withdrawal when injected by an opioid-dependent person (due to naloxone's antagonist effect), but produce no precipitated withdrawal when taken sublingually (because of naloxone's poor bioavailability via the sublingual route). In addition, the optimal combination product also would contain a dose of naloxone that attenuated buprenorphine's agonist effects if injected by a non-opioid dependent person. However, the pharmacologic implications of adding naloxone to buprenorphine are complicated, since parameters such as the doses of naloxone and buprenorphine used, the ratio of the doses, the effects of the product when taken by different routes, and the level of dependence of the subject receiving the product can influence the relative agonist and antagonist effects experienced. Six related human laboratory clinical pharmacology studies of the effects of buprenorphine/naloxone combination products are proposed to address these issues. These studies assess how the addition of naloxone modifies the effects of buprenorphine, how the addition of buprenorphine modifies the effects of naloxone, and how the relative agonist and antagonist effects of buprenorphine/naloxone vary as a function of the level of dependence of subjects. Outcome measures assess the abuse liability of the combination product in dependent and nondependent opioid abusers, the withdrawal precipitation produced by the addition of naloxone, the efficacy of the combination product to suppress acute spontaneous opioid withdrawal, and the efficacy of the combination product to provide acute agonist blockade. Three issues critical to the development of a new medication for drug abuse treatment -- abuse liability, patient acceptability, and therapeutic efficacy -- are addressed in the proposed set of six laboratory studies which will examine the pharmacologic and clinical characteristics of buprenorphine/naloxone.